Masataka Honda

The Impact of Repeated Subclinical Acute Rejection on the Progression of Chronic Allograft Nephropathy

Chronic allograft nephropathy (CAN) is due to both immunologic and non-immunologic factors and results in the development of nonspecific pathologic features that may even be present in long-term well-functioning renal allografts. To investigate the natural history of CAN and potential risk factors associated with progression of these histologic lesions, this study evaluated the of histologic alterations of 124 sequential protocol biopsies performed at 2, 3, and 5 yr after transplantation in 46 patients who exhibited histologic evidence of CAN in the 1-yr biopsy. The occurrence of late acute rejection (AR) greater than 4 mo posttransplant was significantly associated with the development of histologic CAN. In contrast, early clinical AR occurring within 3 mo had no impact on the subsequent development of CAN at 1 yr. Subclinical AR was evident in association with CAN in 50%, 32%, 19%, and 16% of cases with CAN at 1, 2, 3, and 5 yr, respectively. These acute lesions correlated significantly with histologic progression defined as an increased CADI score of the follow-up biopsies. Furthermore, a group of patients who exhibited repeated subclinical AR in the sequential follow-up biopsies had a lower creatinine clearance at 5 yr after transplantation and worse long-term graft survival. In contrast, the absence of evidence of acute inflammation in association with CAN at any time point was associated with minimal deterioration in renal function or progression of renal lesions during the observation period. These results suggest that the persistence of chronic active inflammation may be responsible for the histologic progression of CAN.

Steroid treatment for severe childhood IgA nephropathy: a randomized, controlled trial.

A previous trial showed that treatment of children with severe IgA nephropathy (IgAN) using prednisolone, azathioprine, heparin-warfarin, and dipyridamole for 2 yr early in the course of disease reduced the severity of immunologic renal injury and prevented any increase in the percentage of sclerosed glomeruli. This study compared the effects of prednisolone, azathioprine, warfarin, and dipyridamole (combination) with those of prednisolone alone in 80 children with newly diagnosed IgAN that showed diffuse mesangial proliferation. Patients were randomly assigned to receive either the combination or prednisolone alone for 2 yr. The primary end point was the disappearance of proteinuria, defined as urinary protein excretion <0.1 g/m2 per d, and the secondary end points were urinary protein excretion at the end of treatment, the change in the percentage of sclerosed glomeruli during the trial, and adverse effects. The two study groups were similar in terms of baseline characteristics. Thirty-nine of the 40 patients who received the combination and 39 of the 40 who received prednisolone completed the trial. Thirty-six (92.3%) of the 39 patients who received the combination and 29 (74.4%) of the 39 who received prednisolone reached the primary end point by the 2-yr follow-up point (P = 0.007 log-rank). The percentage of sclerosed glomeruli was unchanged in the patients who received the combination but increased from 3.1 +/- 4.8 to 14.6 +/- 15.2% in the prednisolone group (P = 0.0003). The frequency of adverse effects was similar in the two groups. It is concluded that combination treatment may be better for severe IgAN than treatment with prednisolone alone.

Do intronic mutations affecting splicing of WT1 exon 9 cause Frasier syndrome

The WT1 gene, one of the genes responsible for Wilms tumour, is thought to play a crucial role in the development of the kidneys and gonads. This gene encodes four protein isoforms resulting from two alternative splicing sites, one of which involves inclusion or exclusion of lysine, threonine, and serine (KTS) between the third and fourth zinc finger domains. WT1 is virtually always mutationally inactivated in patients with Denys-Drash syndrome. We analysed WT1 in eight patients who had been diagnosed as having this syndrome, and identified five previously unknown mutations affecting splicing donor sites of intron 9. These mutations affect alternative splicing. The isoforms retaining KTS are not produced. The clinical features of the patients with these intronic mutations were consistent with those of Frasier syndrome, characterised by a more slowly progressive nephropathy than Denys-Drash syndrome, associated streak gonads, and no Wilms tumour development. Our results indicate that WT1 isoforms, including/excluding KTS, have different functions in tumorigenesis and organogenesis of the kidneys and gonads.

Japan renal biopsy registry: The first nationwide, web-based, and prospective registry system of renal biopsies in Japan

BackgroundThe Committee for the Standardization of Renal Pathological Diagnosis and the Working Group for Renal Biopsy Database of the Japanese Society of Nephrology started the first nationwide, web-based, and prospective registry system, the Japan Renal Biopsy Registry (J-RBR), to record the pathological, clinical, and laboratory data of renal biopsies in 2007.MethodsThe patient data including age, gender, laboratory data, and clinical and pathological diagnoses were recorded on the web page of the J-RBR, which utilizes the system of the Internet Data and Information Center for Medical Research in the University Hospital Medical Information Network. We analyzed the clinical and pathological diagnoses registered on the J-RBR in 2007 and 2008.ResultsData were collected from 818 patients from 18 centers in 2007 and 1582 patients from 23 centers in 2008, including the affiliated hospitals. Renal biopsies were obtained from 726 native kidneys (88.8%) and 92 renal grafts (11.2%) in 2007, and 1400 native kidneys (88.5%) and 182 renal grafts (11.5%) in 2008. The most common clinical diagnosis was chronic nephritic syndrome (47.4%), followed by nephrotic syndrome (16.8%) and renal transplantation (11.2%) in 2007. A similar frequency of the clinical diagnoses was recognized in 2008. Of the native kidneys, the most frequent pathological diagnosis as classified by pathogenesis was immunoglobulin (Ig) A nephropathy (IgAN) both in 2007 (32.9%) and 2008 (30.2%). Among the primary glomerular diseases (except IgAN), membranous nephropathy (MN) was the most common disease both in 2007 (31.4%) and 2008 (25.7%).ConclusionsIn a cross-sectional study, the J-RBR has shown IgAN to be the most common disease in renal biopsies in 2007 and 2008, consistent with previous Japanese studies. MN predominated in the primary glomerular diseases (except for IgAN). The frequency of the disease and the clinical and demographic correlations should be investigated in further analyses by the J-RBR.

The 1998 report of the Japanese National Registry data on pediatric end-stage renal disease patients

Abstract We carried out a nationwide survey on patients less than 20 years of age with pediatric chronic end-stage renal disease (ESRD) in Japan for the year 1998. There were 582 patients who had started on renal replacement therapy before 1998, and 105 patients who had been newly introduced to renal replacement therapy in that year. The prevalence rate of the ESRD patients already on treatment was 22 per million population (aged 0–19 years) in 1998. Older patients had a higher prevalence rate than younger ones. There were 345 patients on dialysis as of 1 January 1998, and 237 patients with transplants. The major diseases causing ESRD were renal hypoplasia/dysplasia and focal segmental glomerulosclerosis. Of the 237 patients (46.9%) who had received renal transplants before 1 January 1998, 262 patients (96%) received their transplants from living kidney donors. The incidence rate for the new ESRD patients was 4 per million population (aged 0–19 years) in 1998. Older patients had a slightly higher incidence rate than younger ones. Peritoneal dialysis was used more frequently than hemodialysis under 15 years (85%–95% and 39% respec-tively), especially in very young patients. The major diseases causing ESRD were the same as in the patients already on treatment. The transplant rate for the year 1998 was 10 per 100 dialysis patient-years (patients aged 0–19 years) with 9 living kidney donors. The death rate was 15.6 per 1,000 dialysis patient-years (patients aged 0–19 years); the major causes of death being cardiovascular diseases and infections.

Effective and safe treatment with cyclosporine in nephrotic children: A prospective, randomized multicenter trial

We conducted a prospective, open-label multicenter trial to evaluate the efficacy and safety of treating children with frequently relapsing nephrotic syndrome with cyclosporine. Patients were randomly divided into two groups with both initially receiving cyclosporine for 6 months to maintain a whole-blood trough level between 80 and 100 ng/ml. Over the next 18 months, the dose was adjusted to maintain a slightly lower (60-80 ng/ml) trough level in Group A, while Group B received a fixed dose of 2.5 mg/kg/day. The primary end point was the rate of sustained remission with analysis based on the intention-to-treat principle. After 2 years, the rate of sustained remission was significantly higher while the hazard ratio for relapse was significantly lower in Group A as compared with Group B. Mild arteriolar hyalinosis of the kidney was more frequently seen in Group A than in Group B, but no patient was diagnosed with striped interstitial fibrosis or tubular atrophy. We conclude that cyclosporine given to maintain targeted trough levels is an effective and relatively safe treatment for children with frequently relapsing nephrotic syndrome.

Age, gender, and body length effects on reference serum creatinine levels determined by an enzymatic method in Japanese children : a multicenter study

BackgroundEnzymatic methods have recently been used to measure creatinine (Cr) instead of the Jaffe method. Therefore, it is necessary to determine the reference serum Cr value for these enzymatic methods to evaluate renal function in Japanese children.MethodsTo determine reference values of serum Cr in Japanese children, 1151 children (517 male, 634 female) aged between 1 month and 18 years had their serum Cr values measured by an enzymatic method. To be included in the study the children had to be without kidney disease, urogenital disease, infectious disease, inflammatory disease, dehydration, muscular disease, anomaly syndrome, cardiovascular disease, malignant disease, hypertension, liver or pancreas disease, or pregnancy.ResultsThe medians of reference values increased gradually with age, i.e., 0.30 mg/dl at 4 years old and 0.41 mg/dl at 10 years old. In adolescence, they increased significantly more rapidly in males than in females. We found a linear regression equation capable of estimating the reference value of serum Cr in children aged 2–11 years, and quintic regression equations capable of estimating the reference values of serum Cr in male and female children of all ages.ConclusionThe reference serum Cr levels determined by an enzymatic method related to age, gender, and body length, and our linear and polynomial equations showing the relationship between body length and serum Cr level will be applicable for screening of renal function in Asian as well as Japanese children.

Nephrotic state as a risk factor for developing posterior reversible encephalopathy syndrome in paediatric patients with nephrotic syndrome

BACKGROUND Posterior reversible encephalopathy syndrome (PRES) is a distinctive and potentially serious complication of the nephrotic syndrome. The objective of the present study is to characterize the factors predisposing the development of PRES in paediatric patients with nephrotic syndrome. METHODS We investigated paediatric patients with idiopathic nephrotic syndrome who developed PRES between 1999 and 2005 in our institution. Patients with steroid-sensitive nephrotic syndrome and those with steroid-resistant nephrotic syndrome that were proven to be idiopathic were eligible. RESULTS In total, seven patients ranging in age from 1.5 to 15.1 years old were analysed. At the onset of PRES, six of the seven patients were in a nephrotic state. Various degrees of acute renal insufficiency were shown in four patients. The re-administration of cyclosporine after the episodes of PRES was carried out in four patients. During the observation for 17-51 months after the re-administration, the recurrence of PRES did not develop in these patients. CONCLUSIONS The development of PRES occurred at the time of moderate to severe nephrotic state in most of our paediatric patients with nephrotic syndrome. Besides the administration of cyclosporine and having hypertension, there appear to be several additive factors predisposing the development of PRES in these patients, namely low serum albumin level, generalized oedema, increase in vascular permeability, unstable fluid status and renal insufficiency. The re-administration of cyclosporine to those patients with anamnesis of PRES may be considered after the management and close monitoring of these factors as well as hypertension.

Reversible posterior leukoencephalopathy in a patient with minimal-change nephrotic syndrome

A 9-year-old boy with nephrotic syndrome was transferred to our hospital because of acute renal failure and disturbance of consciousness after high-dose methylprednisolone therapy. He developed severe headache, visual disturbance, and generalized seizures. Brain computed tomography (CT) scan revealed multiple, bilateral, low-density areas in the parieto-occipital lobes. Magnetic resonance imaging (MRI) disclosed a high signal intensity area on T2-weighted images and a low signal intensity area on T1-weighted images in the same lesion. Follow-up brain CT scan and MRI, 2 weeks after the first studies, showed complete resolution of the abnormal lesions, which suggested the diagnosis of reversible posterior leukoencephalopathy syndrome (RPLS). Hypertension and high-dose methylprednisolone administration to the patient in the nephrotic state may be causes of this uncommon syndrome in this case. This is the first report of RPLS in nephrotic syndrome with hypertension not associated with cyclosporine administration.

A multicenter randomized trial indicates initial prednisolone treatment for childhood nephrotic syndrome for two months is not inferior to six-month treatment

In this multicenter, open-label, randomized controlled trial, we determined whether 2-month prednisolone therapy for steroid-sensitive nephrotic syndrome was inferior or not to 6-month therapy despite significantly less steroid exposure. The primary end point was time from start of initial treatment to start of frequently relapsing nephrotic syndrome. The pre-specified non-inferiority margin was a hazard ratio of 1.3 with one-sided significance of 5%. We randomly assigned 255 children with an initial episode of steroid-sensitive nephrotic syndrome to either 2 - or 6-month treatment of which 246 were eligible for final analysis. The total prednisolone exposure counted both initial and relapse prednisolone treatment administered over 24 months. Median follow-up in months was 36.7 in the 2-month and 38.2 in the 6-month treatment group. Time to frequent relaps was similar in both groups; however, the median was reached only in the 6-month group (799 days). The hazard ratio was 0.86 (90% confidence interval, 0.64–1.16) and met the non-inferior margin. Time to first relapse was also similar in both groups: median day 242 (2-month) and 243 (6-month). Frequency and severity of adverse events were similar in both groups. Most adverse events were transient and occurred during initial or relapse therapy. Thus, 2 months of initial prednisolone therapy for steroid-sensitive nephrotic syndrome, despite less prednisolone exposure, is not inferior to 6 months of initial therapy in terms of time to onset of frequently relapsing nephrotic syndrome.